P769: MUTATION PROFILES AND RISK STRATIFICATION IN HYPOCELLULAR MYELODYSPLASTIC SYNDROME
Authors: K. Kim, K. Chien, O. Faustine, G. Montalban-Bravo, R. Kanagal-Shamanna, T. Kadia, E. Jabbour, Y. Alvarado, K. Sasaki, X. Q. Dong, S. Pierce, C. Bueso-Ramos, H. Kantarjian, G. Garcia-Manero
Journal: HemaSphere (2022)

Background: Hypocellular myelodysplastic syndrome (hMDS) is a subset of MDS, defined by marrow cellularity less than 30% in age under 70 and less than 20% in age 70 or more. The clinicopathologic features of hMDS have been previously studied, but genetic data and clinical impact of hMDS remain unclear. Aims: We conducted a comparative study of hMDS to normo-/hypercellular MDS (non-hMDS) with clinical characteristics and mutations and further stratified the risk by mutation profile. Methods: We conducted a retrospective review using a single tertiary cancer center registry of untreated MDS patients from 2020 to 2021. Mutation data was obtained by 28- or 81-gene next-generation sequencing (NGS) panels. We analyzed clinicopathological and mutation data comparing hMDS to non-hMDS pts and conducted risk stratification in hMDS using mutation profiles. Results: In a total of 1899 patients, 174 (9%) patients had hMDS. 1352 (71%) pts had mutation profiles that were further analyzed; 56% and 44% patients had 81-gene and 28-gene NGS panels performed, respectively. The median follow-up time was 19.5 months. Thrombocytopenia (p=0.016) and neutropenia (p<0.0001) were more common in hMDS than in non-hMDS. By IPSS-R cytogenetic scores, hMDS had scores of 3 than non-hMDS (20% vs. 9%, p<0.001), but non-hMDS had more cytogenetic scores of 4 (27% vs. 19%, p=0.018). The distribution of other IPSS-R cytogenetic scores or IPSS-R risk classifications was similar between the 2 groups. hMDS patients were more likely to be age<65 (68% vs. 47%, p<0.001) and have therapy-related MDS (t-MDS) (44% vs. 32%, p=.001). hMDS patients also had a median overall survival (mOS) of 29.2 months, which was similar to that observed in non-hMDS pts (HR 1.04, p=0.702). This finding was maintained after multivariate adjustment including age, IPSS-R, t-MDS, and certain high-risk mutations (TP53, ASXL1, RUNX1, RAS pathway). Hypocellularity did not affect survival in either de novo or t-MDS. AML transformation rates (20% in both groups) were similar. Interestingly, pts with hMDS had lower rates of high-risk mutations (38% vs. 51%, p=0.009) with less RUNX1 (p=0.079) and ASXL1 (p=0.010) mutations while the frequency of TP53 and RAS pathway mutations were comparable. In t-MDS, hMDS pts had less frequent TP53 (p=0.005) or U2AF1 (p=0.087) mutations. In de novo MDS, hMDS patients had less RUNX1 (p=0.036), SRSF2 (p=0.014), and TET2 (p=0.019) mutations. In hMDS, mutations in the RAS pathway (HR 3.64, p=0.007) or in TP53 (HR 2.47, p=0.002) were associated inferior mOS, while TET2 mutations (HR 0.29, p=0.036) correlated with superior mOS. hMDS also had worse mOS in RAS pathway-mutated MDS (HR 2.62, p=0.043). Based on mutation data and multivariate selection models, patients were stratified into 3 groups: (1) pts with TET2 or SF3B1 (only available 81-gene panels) mutations, (2) pts with TP53 mutations or RAS pathway mutations, and (3) pts without TET2/SF3B1/TP53/RAS mutations. The TET2/SF3B1 group showed better mOS (HR 0.34, p=0.041) compared to the TP53/RAS group showing inferior mOS (HR 4.64, p<0.001) (shown in figure). The mOS difference observed with the TET2/SF3B1 group did not carry over into non-hMDS pts (p=0.889). Image:Summary/Conclusion: Our study showed that hMDS patients have similar outcomes with non-hMDS pts with unique molecular profiles. hMDS pts have less frequent high-risk mutations with distinct risk stratification. Improving risk stratification tools in hMDS by incorporating genomic data, such as TP53/RAS pathway and TET2/SF3B1 mutations, would be a study of interest.